Oxygen tension distribution is not homogeneous within a solid tumor, inside which tumor cells are exposed to various oxygen environments. This arises from limitations in the distance by which oxygen molecules diffuse from blood vessels to the tumor tissue.
As is known, expression of target genes such as therapeutic genes, reporter genes and the like can be induced in a hypoxic environment by using hypoxia-responsive enhancers such as HREs or the like.
However, such gene expression systems were problematic in that the genes are expressed also, although slightly, in aerobic conditions. Moreover, response in real time to the oxygen environment in which the cell is placed was difficult owing to the stability of reporter genes. Specifically, there were no reporters that, although capable of sensing a hypoxic stimulus in an existing system, did sense thereafter an aerobic stimulus (re-oxygenation) in a short lapse of time, and hence it was not possible to reflect in real time the oxygen environment in which the cells were placed. As is known, moreover, such hypoxia-responsive promoters are activated not only in a hypoxic environment, but also in some abnormal cells that result, directly or indirectly, from the hypoxic environment. In light of the possibility of sensing various disease conditions that result directly or indirectly from a hypoxic environment, therefore, there was a strong interest in the development of gene expression systems that should have high responsiveness to environments that are intimately involved in a disease condition.
Patent documents 1 and 2 disclose a combination of a reporter gene and a hypoxia inducible promoter (HRE), but recite nothing concerning ODD.
Patent document 3 discloses a combination of a reporter gene and NLS-ODD, but recites nothing concerning a hypoxia inducible promoter (HRE).
Patent document 1: Japanese Translation of PCT Application H11-506302
Patent document 2: Japanese Translation of PCT Application 2004-509635
Patent document 3: WO2002/099104